Date of Award

1975

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacy and Toxicology

First Advisor

Harbans Lal

Abstract

This research investigated the pharmacological alteration of drug-induced aggression in naive, morphine-dependent and chronically haloperidol treated rats. Naive rats were treated with apomorphine (1.25 - 20 mg/Kg) and aggregated in groups of four for aggression. It was determined that 20 mg/Kg of apomorphine produced maximal aggression, as measured by number of attacks, duration of aggressive posturing and number of vocalizations. Doses less than 5 mg/Kg were without any effect. The neuroleptics, haloperidol and oxyperomide, the narcotic, morphine, and the cholinergic agonist, pilocarpine all reduced apomorphine-induced aggression in a dose dependent manner. Centrally acting anti-cholinergic drugs partially reversed the blockade of aggression produced by all the drugs except morphine which was preferentially antagonized by naloxone, a narcotic antagonist. Aggression was elicited by sub-threshold doses of apomorphine when combined with clonidine; large doses of dexetimide, an anticholinergic; or when administered three days after an injection of p-chloroamphetamine (12 mg/Kg). None of these drugs were capable of eliciting aggression by themselves. Amphetamine potentiated the apomorphine-induced aggression, but failed to elicit aggression with sub-threshold doses of apomorphine unless combined with cyproheptadine.

In morphine-dependent rats, aggression was observed during withdrawal produced by withholding of injections, but not in withdrawal induced by naloxone. The aggression - which was observed at 72 hours and at 30 days of withdrawal - was reduced by morphine, haloperidol or by lesions of the dopaminergic nigro-striatal bundle, and enhanced by small doses of apomorphine. Apomorphine was also capable of eliciting aggression when administered at four hours of withdrawal, with or without naloxone. The 72 hour withdrawal aggression was similar to apomorphine-induced aggression in naive rats since it was dose-dependently increased by dexetimide or clonidine and decreased by pilocarpine. However, in contrast to the effect in naive rats, anticholinergic drugs failed to reverse the blockade of aggression produced by haloperidol in morphine dependent rats.

Following chronic treatment with haloperidol, rats demonstrated signs of dopaminergic supersensitivity as shown by enhanced apomorphine- or amphetamine-induced stereotypy, increased spontaneous hyperactivity and a shift to the left of the dose-response curve for amphetamine stimulation and for apomorphine-induced reduction in striatal dopamine turnover. In addition, the rats exhibited an increased sensitivity to the stimulation of activity produced by dexetimide and a decrease in the depression of activity produced by pilocarpine. Although there was no spontaneous aggression after discontinuation of chronic halperidol, the threshold dose of apomorphine required to elicit aggression was dramatically reduced. Amphetamine failed to produce aggression after chronic haloperidol, in contrast to the effect normally seen after chronic morphine.

The results of this study demonstrated the requirement of central dopaminergic stimulation for drug-induced aggression, and suggested that the aggression was antagonized by the activity of acetylcholine and serotonin and possibly facilitated by norepinephrine. In addition, it suggested that morphine and haloperidol produce an anti-aggression action by different mechanisms, possibly involving a cholinergic component in the case of haloperidol. Finally, the research provided evidence that the dopaminergic supersensitivity following chronic treatment with morphine may be qualitatively or quantitatively different from the supersensitivity following chronic treatment with haloperidol, since spontaneous and amphetamine stimulated aggression are noted only in the former case. It was proposed that morphine interferes with cholinergic and/or serotonergic compensatory mechanisms and that these contribute to the aggression.

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